The present invention relates to the targeting of a therapeutic effector to a biomedical device and, in particular, to the use of radioimmunotherapy for the localization of radioactivity to stents for the reduction or elimination of restenosis.
Restenosis of blood vessels occurs after narrowed or occluded arteries are forcibly dilated by balloon catheters, drills, lasers and the like, in a procedure known as angioplasty. Such forcible dilation is required in order to reopen arteries which have been narrowed or occluded by atherosclerosis. However, up to 45% of all arteries which have been treated by angioplasty return to their narrowed state through the process of restenosis. Restenosis is caused by a number of mechanisms, such as recoil of the vessel wall towards its original dimensions, neointimal hyperplasia induced by trauma to the vessel wall, accumulation of extracellular matrix, remodeling of the tissue and other biological processes. Restenosis can significantly reduce the efficacy of angioplasty and as such is a major barrier to the effective treatment of narrowed arteries.
Attempts to reduce or eliminate restenosis have generally focused on the insertion of biomedical devices, such as stents, within the treated artery. Stents can reduce restenosis by preventing recoil of the treated blood vessel to its original dimensions. Various stents are known in the art, including coils and sleeves, those which are expandable by balloon catheters, heat expandable and self-expandable stents. Unfortunately, stents alone cannot prevent restenosis caused by neointimal hyperplasia of the tissues of the vessel wall. In fact, the stent material itself may accelerate such hyperplasia, since it is foreign to the body tissues.
Recently, as noted above, radionuclear irradiation of blood vessels has been proposed as a method of preventing restenosis caused by neointimal hyperplasia. The application of radionuclear irradiation to the body of a subject is a well accepted mode of therapy in medicine. The main use of such irradiation is for treating both malignant and benign tumors. Radionuclear irradiation can also be used to inhibit the undesired proliferation of cells in other rapidly growing tissues, such as keloids and blood vessels undergoing restenosis.
One study showed that such irradiation completely prevented restenosis of the treated arteries [H. D. Bottcher et al., Int. J. Radiation Oncology Biol. Phys., 29:183-186, 1994]. A number of studies in animal models also support the efficacy of radionuclear irradiation of blood vessels for the prevention or reduction of restenosis following angioplasty [J. G. Wiedermann et al., JACC, 23:1491-8, 1994; R. Waksman et al., Circulation, 92:3025-3031, 1995; R. Waksman et al., Circulation, 91:1533-1539, 1995]. Thus, clearly exposing the walls of blood vessels to radioactivity is a valuable method of preventing and treating restenosis caused by neointimal hyperplasia.
Currently, radionuclear irradiation of blood vessels is performed by the insertion of temporary or permanent radionuclear sources into the vessels. For example, radioactive yttrium-90 wires were inserted into the central lumen of a balloon catheter in order to irradiate blood vessel walls [Y. Popowski et al., Int. J. Radiation Oncology Biol. Phys., 43:211-215, 1995]. Other radioactive sources have included iridium-192, administered by catheter to arteries which had been treated by angioplasty [P. S. Teirstein et al, Circulation, 94:I-210, 1996]. U.S. Pat. No. 5,213,561 discloses a device for inserting a radionuclear source into a blood vessel, in which the source of radioactivity is mounted on a stent, for example.
Unfortunately, the insertion of radionuclear sources directly attached a catheter or stent, in which the catheter or stent is radioactive prior to insertion into the blood vessel, has a number of disadvantages. First, such procedures require a highly specialized clinical setting, which is appropriate both for catheterization procedures and for the handling of radioactivity. Second, these procedures are highly invasive. Third, temporary radioactive sources require repeated invasive treatments. However, temporary as well as permanent sources have the further disadvantage of decaying according to their specific half-life. Thus, current methods for irradiating blood vessels have significant disadvantages.
The concept of specifically targeting tumor cells is a goal of modem radio-oncology. The developing field of radiolabelled immunoglobulin therapy (RIT) employs radionuclide-labeled monoclonal antibodies which recognize tumor-associated antigens, thereby selectively targeting tumor cells. Beta particles, alpha particles and gamma rays emitted from a radiolabelled antibody bound to a tumor cell also kill neighboring cells because these particles can penetrate through several cell diameters. In B-cell lymphoma refractory to chemotherapy, RIT has been associated with a high rate of durable remissions [Kaminki et al., JCO, 14:1974-1981, 1996].
RIT may be effective for cancer treatment because tumor cells have special antigens on their surface, against which antibodies can be raised. Unfortunately, the situation is much more complicated for the prevention and treatment of restenosis. Restenotic tissue is not known to express special antigens, to that antibodies against such tissue would also bind to normal blood vessel walls and would not be sufficiently specific for the tissue to be treated. Thus, targeting antibodies directly to the tissue itself is not possible.
However, the specific targeting of effector moieties to restenotic tissue would have many benefits for the treatment and prevention of restenosis. For example, a targeted drug or an isotope could be injected into the patient at a site distant from the catheterized blood vessel. The targeted drug or isotope would remain in the area of catheterization, specifically treating the restenotic tissue without serious or problematic side effects. Furthermore, the targeted effector could be injected substantially after catheterization, which would permit the effector to be injected at a different location. For example, if the effector was an isotope, the injection could be performed in a special facility for treatment with radioactivity. In addition, the effector could potentially be selected according to the degree of severity of restenosis, which could be monitored after the insertion of the catheter or stent. Thus, the separation of the procedures for catheterization and for treatment with an effector would clearly increase the flexibility of treatment for restenosis.
Of course, restenosis is not the only pathological condition which could benefit from treatment with a targeted effector. Other types of biomedical devices can cause pathological overgrowth or ingrowth of tissue surrounding the insertion point of the device. Such pathological tissue growth in the area of an inserted biomedical device can be difficult to treat, as these devices are not always immediately accessible through surgery, for example. Treatment with a targeted effector, which would be specifically localized to the tissue surrounding the biomedical device without the requirement for additional surgery, would clearly be highly beneficial. Moreover, such a device may be purposefully implanted into a tumor in order to provide highly localized treatment of malignancies, particularly for solid tumors.
There is thus a widely recognized need for, and it would be highly advantageous to have, a method of targeting an effector, such as a radioactive isotope, to specific areas near an inserted biomedical device, such as a blood vessel, in order to perform localized therapy for the treatment or prevention of a pathological condition, such as restenosis of a catheterized blood vessel.